Description:

Objective:

The objective of this research project is to identify susceptibility factors for developmental neurotoxicity of pesticides, including genetic polymorphisms.

Progress Summary:

During the reporting period, we completed our studies on histopathological changes in the neocortex of mice following postnatal exposure to chlorpyrifos-oxon (CPO). In paraoxonase (PON1)-knockout mice exposed to 0.18 or 0.25 mg/kg/day CPO from postnatal day (PND) 4 to 21, we had observed histopathology in the neocortex, characterized by perinuclear vacuolization and alteration of the endoplasmic reticulum. We followed up on this observation by exposing hPON1Q192 and hPON1R192 transgenic mice to CPO at the same dosage levels, and assessing neuropathology at PND 13, 22, and 90. As we had hypothesized, changes in the transgenic animals exposed to CPO were less severe than those observed in PON1-knockout mice, and hPON1Q192 mice were more sensitive than hPON1R192 mice (Table 1).

Table 1. Perinuclear Vacuoles in Neocortex of PON1 Mice Exposed to CPO During Postnatal Development

We are nearing completion of studies of acute organophosphorus pesticide (OP) toxicity in developing hPON1Q192 and hPON1R192 mice. These studies involved a single subcutaneous injection of CPO followed by measurement of acetylcholinesterase activity in the brain, diaphragm, and plasma. Dose-response curves have been completed for CPO and chlorpyrifos (CPS) at PND 13, 21, and 40. Currently, we are repeating the CPO dose-response curve at PND 4 and beginning experiments with diazinon (DZ) and diazoxon (DZO).

Significance

A potentially important finding is the presence of histopathological changes in the neocortex of mice following postnatal exposure to CPO, with greater protection afforded by hPON1R192 compared to hPON1Q192.

Future Activities:

In the next year, we will continue our studies assessing the possible presence of apoptotic changes in CPO-treated mice, using caspase staining. The observed changes are suggestive of abnormal apoptosis in specific brain regions following developmental CPO exposure. Our neurobehavioral studies in the previous reporting period had revealed no behavioral changes following chronic CPO exposure. In the next year, we will test CPO-exposed mice in an open field/emergence/novel object test designed to measure complex behavior and memory. There is some suggestion from the literature that these behaviors may be more likely to be affected by OP exposure. We will finish the studies of acute CPO and CPS exposure in developing mice and focus on the effects of DZ and DZO exposures.

Subprojects under this Center:(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).R831709C001 Molecular Mechanisms of Pesticide-Induced Developmental ToxicityR831709C002 Genetic Susceptibility to PesticidesR831709C003 Community-Based Participatory Research ProjectR831709C004 Pesticide Exposure Pathways Research Project

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.